Human Peptides α-Defensin-1 and -5 Inhibit Pertussis Toxin

Kling, Carolin; Pulliainen, Arto T.; Barth, Holger; Ernst, Katharina

doi:10.3390/toxins13070480

Cited by 4 publications

(8 citation statements)

References 46 publications

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“…Recently, the human antimicrobial peptides α-defensin-1 and -5 have been identified as inhibitors of PT activity [ 51 ]. Defensins are part of the innate immunity and are characterized as small, cationic and cysteine-rich peptides.…”

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

“…ADP-ribosylation of Gαi leads to its inactivation and thereby loss of adenylate cyclase inhibition upon receptor stimulation ( Figure 1 ). In a novel living cell-based interference in Gαi-mediated signal transduction (iGIST) assay, the effect of PT on Gαi and thereby cAMP signaling was measured [ 41 , 51 , 86 ]. This assay is based on HEK293 cells that express the somatostatin receptor 2 (SSTR2), which is a Gαi-protein coupled receptor (GPCR), as well as a luminescent cAMP probe.…”

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

“…This is because PTS1 inactivates Gαi of SSTR2 by ADP-ribosylation. α-defensin-1 and -5 both reduced PT-mediated effects on cAMP levels in this novel bioassay indicating that the defensins interfered with PT activity [ 51 ].…”

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

“…Unlike α-defensin-1 and -5, ß-defensin-1 had no effect on in vitro enzyme activity, intoxication of cells or PT-mediated effects on cAMP signaling [ 51 ]. This suggests a specific inhibition mechanism of α-defensin-1 and -5 on PT activity.…”

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

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Novel Strategies to Inhibit Pertussis Toxin

Ernst

2022

Toxins

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Pertussis, also known as whooping cough, is a respiratory disease caused by infection with Bordetella pertussis, which releases several virulence factors, including the AB-type pertussis toxin (PT). The characteristic symptom is severe, long-lasting paroxysmal coughing. Especially in newborns and infants, pertussis symptoms, such as leukocytosis, can become life-threatening. Despite an available vaccination, increasing case numbers have been reported worldwide, including Western countries such as Germany and the USA. Antibiotic treatment is available and important to prevent further transmission. However, antibiotics only reduce symptoms if administered in early stages, which rarely occurs due to a late diagnosis. Thus, no causative treatments against symptoms of whooping cough are currently available. The AB-type protein toxin PT is a main virulence factor and consists of a binding subunit that facilitates transport of an enzyme subunit into the cytosol of target cells. There, the enzyme subunit ADP-ribosylates inhibitory α-subunits of G-protein coupled receptors resulting in disturbed cAMP signaling. As an important virulence factor associated with severe symptoms, such as leukocytosis, and poor outcomes, PT represents an attractive drug target to develop novel therapeutic strategies. In this review, chaperone inhibitors, human peptides, small molecule inhibitors, and humanized antibodies are discussed as novel strategies to inhibit PT.

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Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

Section: Novel Inhibitors Of Pertussis Toxinmentioning

confidence: 99%

See 2 more Smart Citations

Novel Strategies to Inhibit Pertussis Toxin

Ernst

2022

Toxins

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“…Recently, we identified the human antimicrobial peptides α-defensin-1 and α-defensin-5, also known as human neutrophil peptide 1 (HNP1) and human defensin-5 (HD5), respectively, as inhibitors of PT [ 35 ]. Defensins are small, cationic, and cysteine-rich peptides with a crucial role in innate immunity by inactivating bacterial pathogens [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Pertussis Toxin by Human α-Defensins-1 and -5: Differential Mechanisms of Action

Kling

Sommer

Almeida-Hernández

et al. 2023

IJMS

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Whooping cough is a severe childhood disease, caused by the bacterium Bordetella pertussis, which releases pertussis toxin (PT) as a major virulence factor. Previously, we identified the human antimicrobial peptides α-defensin-1 and -5 as inhibitors of PT and demonstrated their capacity to inhibit the activity of the PT enzyme subunit PTS1. Here, the underlying mechanism of toxin inhibition was investigated in more detail, which is essential for developing the therapeutic potential of these peptides. Flow cytometry and immunocytochemistry revealed that α-defensin-5 strongly reduced PT binding to, and uptake into cells, whereas α-defensin-1 caused only a mild reduction. Conversely, α-defensin-1, but not α-defensin-5 was taken up into different cell lines and interacted with PTS1 inside cells, based on proximity ligation assay. In-silico modeling revealed specific interaction interfaces for α-defensin-1 with PTS1 and vice versa, unlike α-defensin-5. Dot blot experiments showed that α-defensin-1 binds to PTS1 and even stronger to its substrate protein Gαi in vitro. NADase activity of PTS1 in vitro was not inhibited by α-defensin-1 in the absence of Gαi. Taken together, these results suggest that α-defensin-1 inhibits PT mainly by inhibiting enzyme activity of PTS1, whereas α-defensin-5 mainly inhibits cellular uptake of PT. These findings will pave the way for optimization of α-defensins as novel therapeutics against whooping cough.

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The antiarrhythmic drugs amiodarone and dronedarone inhibit intoxication of cells with pertussis toxin

Jia,

Lietz,

Barth

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Pertussis toxin (PT) is a virulent factor produced by Bordetella pertussis, the causative agent of whooping cough. PT exerts its pathogenic effects by ADP-ribosylating heterotrimeric G proteins, disrupting cellular signaling pathways. Here, we investigate the potential of two antiarrhythmic drugs, amiodarone and dronedarone, in mitigating PT-induced cellular intoxication. After binding to cells, PT is endocytosed, transported from the Golgi to the endoplasmic reticulum where the enzyme subunit PTS1 is released from the transport subunit of PT. PTS1 is translocated into the cytosol where it ADP-ribosylates inhibitory α-subunit of G-protein coupled receptors (Gαi). We showed that amiodarone and dronedarone protected CHO cells and human A549 cells from PT-intoxication by analyzing the ADP-ribosylation status of Gαi. Amiodarone had no effect on PT binding to cells or in vitro enzyme activity of PTS1 but reduced the signal of PTS1 in the cell suggesting that amiodarone interferes with intracellular transport of PTS1. Moreover, dronedarone mitigated the PT-mediated effect on cAMP signaling in a cell-based bioassay. Taken together, our findings underscore the inhibitory effects of amiodarone and dronedarone on PT-induced cellular intoxication, providing valuable insights into drug repurposing for infectious disease management.

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Human Peptides α-Defensin-1 and -5 Inhibit Pertussis Toxin

Cited by 4 publications

References 46 publications

Novel Strategies to Inhibit Pertussis Toxin

Novel Strategies to Inhibit Pertussis Toxin

Inhibition of Pertussis Toxin by Human α-Defensins-1 and -5: Differential Mechanisms of Action

The antiarrhythmic drugs amiodarone and dronedarone inhibit intoxication of cells with pertussis toxin

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